Sulfonamide derivatives, preparation and therapeutic application thereof

Abstract

The present invention is directed to a compound of formula (I): wherein Ar 1 , Ar 2 , Ar 3 , R, R′ and T are as defined herein, its preparation, pharmaceutical composition and uses as orexin 2 receptor antagonist.

1 . A compound of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein:
 R is a hydrogen atom or a (C 1 -C 4 )alkyl group; 
 R′ is a (C 1 -C 4 )alkyl group optionally substituted by one or more groups chosen from:
 a hydroxyl group, 
 a halogen group, 
 a (C 1 -C 4 )alkoxy group, 
 an aryloxy group, optionally substituted by one or more groups chosen from a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, 
 an aryl group, optionally substituted by one or more groups chosen from a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, 
 an —NH(COO)R a  group, wherein R a  is a (C 1 -C 4 ) alkyl group; 
 an —NH(CO)R b  group, wherein R b  is a (C 1 -C 4 )alkyl or an aryl group, and the said aryl group is optionally substituted by one or more groups chosen from a halogen atom, or a (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or carboxylic acid group, 
 an —NR c R d  or —CONR c R d  group, wherein R c  and R d  are independently of one another a hydrogen atom or a (C 1 -C 4 )alkyl group, or R c  and R d  taken together with the nitrogen atom to which they are attached form a heterocyclyl group, 
 an —NR f R g R h  ammonium group, wherein R f , R g  and R h  are a (C 1 -C 4 )alkyl group, 
 a heterocyclyl group, or 
 a —COOR e  group, wherein R e  is a hydrogen atom or a (C 1 -C 4 )alkyl group, or 
 a —COOH, —COO(C 1 -C 4 )alkyl, or —CONR c R d  group 
 
 Ar 1  is an aryl group optionally substituted by one or more groups chosen, independently of one another, from a halogen atom, cyano, or a (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, or
 a heterocyclyl group optionally substituted by a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 ) alkoxy group; 
 
 T is a —(CH 2 ) n — group, wherein n=1 or 2, or
 a group: 
 
 
     
       
         
         
             
             
         
       
       Ar 2  is an aryl group optionally substituted by one or more groups chosen, independently of one another, from a halogen atom, or a (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, fluoro(C 1 -C 4 )alkyl or fluoro(C 1 -C 4 )alkoxy group, or
 a heterocyclyl group optionally substituted by a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 ) alkoxy group; and 
 
       Ar 3  is an aryl group optionally substituted by one or more groups chosen, independently of one another, from a halogen atom, a hydroxyl group, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, or
 a heterocyclyl group optionally substituted by a hydroxyl group, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, fluoro(C 1 -C 4 )alkyl or fluoro(C 1 -C 4 )alkoxy group; 
 
     
     or an addition salt with an acid thereof, or a hydrate or solvate thereof. 
   
   
       2 . The compound according to  claim 1 , wherein:
 R′ is a (C 1 -C 4 )alkyl group optionally substituted by one or more groups chosen from:
 a hydroxyl group, 
 a halogen group, 
 a (C 1 -C 4 )alkoxy group, 
 an aryloxy group, optionally substituted by one or more groups chosen from a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, 
 an aryl group, optionally substituted by one or more groups chosen from a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, 
 an —NH(COO)R a  group, wherein R a  is a (C 1 -C 4 ) alkyl group, 
 an NH(CO)R b  group, wherein R b  is an aryl group optionally substituted by one or more groups chosen from a halogen atom, or a (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy or carboxylic acid group, 
 an —NR c R d  or —CONR c R d  group, wherein R c  and R d  are independently of one another a hydrogen atom or a (C 1 -C 4 )alkyl group, or R c  and R d  taken together with the nitrogen atom to which they are attached form a heterocyclyl group, 
 an —NR f R g R h  ammonium group, wherein R f , R g  and R h  are a (C 1 -C 4 )alkyl group, 
 a heterocyclyl group, or 
 a COOR e  group, wherein R e  is a hydrogen atom or a (C 1 -C 4 )alkyl group, or 
 a —COO(C 1 -C 4 ) alkyl or —CONR c R d  group; 
   Ar 1  is phenyl or naphthyl, each of which is optionally substituted by one or more groups chosen, independently of one another, from a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, or
 pyridinyl or pyrimidinyl, each of which is optionally substituted by a halogen atom, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy; 
   T is a —CH 2 — group;   Ar 2  is phenyl, or naphthyl, each of which is optionally substituted by one or more groups chosen, independently of one another, from a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, or
 pyridinyl, optionally substituted by a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group; and 
   Ar 3  is phenyl or naphthyl, each of which is optionally substituted by one or more groups chosen, independently of one another, from a halogen atom, or a hydroxyl, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, or
 pyridinyl or furanyl, each of which is optionally substituted by a hydroxyl, (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy group; 
   
     or an addition salt with an acid thereof, or a hydrate or solvate thereof. 
   
   
       3 . The compound according to  claim 1 :
 R′ is a (C 1 -C 4 )alkyl group optionally substituted by one or more groups chosen from:
 a hydroxyl group, 
 a (C 1 -C 4 )alkoxy group, 
 an aryloxy group, optionally substituted by one or more groups chosen from a halogen atom, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy, 
 an aryl group, optionally substituted by one or more groups chosen from a halogen atom, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy, 
 an NH(CO)R b  group, wherein R b  is an aryl group optionally substituted by one or more carboxylic acid groups, 
 an —NR c R d  or —CONR c R d  group, in which R c  and R d  are independently of one another: a hydrogen atom or (C 1 -C 4 )alkyl, or R c  and R d  taken together with the nitrogen atom to which they are attached form a heterocyclyl, 
 a heterocyclyl group, or 
 a COOR e  group, wherein R e  is a hydrogen atom or a (C 1 -C 4 )alkyl group, or 
 a —COO(C 1 -C 4 )alkyl, or —CONR c R d  group; 
   Ar 1  is phenyl optionally substituted by one or more groups chosen, independently of one another, from a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, or
 Pyridinyl optionally substituted by a (C 1 -C 4 ) alkyl group; 
   T is a —CH 2 — group;   Ar 2  is phenyl optionally substituted by one or more groups chosen, independently of one another, from a halogen atom, (a C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, or
 pyridinyl optionally substituted by a halogen atom, or a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group; and 
   Ar 3  is phenyl optionally substituted by one or more groups chosen, independently of one another, from a halogen atom, or a hydroxyl, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, or
 pyridinyl or furanyl, each of which is optionally substituted by a hydroxyl, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group; 
   
     or an addition salt with an acid thereof, or a hydrate or solvate thereof. 
   
   
       4 . A process for preparing the compound according to  claim 1 , comprising condensing an epoxide of formula (X), in a basic medium, with a compound of formula (II): 
     
       
         
         
             
             
         
       
     
     Wherein Ar 1 , Ar 2 , Ar 3 , T, R and R′ are as defined in  claim 1 . 
   
   
       5 . The process according to  claim 4 , wherein the compound of formula (II) is prepared by sulfonylating a compound of formula (III) with a sulfonyl chloride of formula (V) in the presence of a base: 
     
       
         
         
             
             
         
       
     
   
   
       6 . A method for treating obesity, appetite or taste disturbance, cachexia, anorexia, bulimia, diabetes, metabolic syndrome, vomiting, nausea, depression, anxiety, addiction, mood or behavioral disorder, schizophrenia, sleep disorder, restless leg syndrome, learning or memory disorder, sexual or psychosexual dysfunction, pain, visceral or neuropathic pain, hyperalgesia, allodynia, digestive disorder, irritable bowel syndrome, neuronal degeneration, ischemic or hemorrhagic strokes, Cushing's disease, Guillain-Barré syndrome, myotonic dystrophy, urinary incontinence, hyperthyroidism, disorder of pituitary function, hypertension or hypotension, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 1 , or an addition salt with an acid thereof, or a hydrate or solvate thereof. 
   
   
       7 . A method for treating obesity, appetite or taste disturbance, cachexia, anorexia, bulimia, diabetes, metabolic syndrome, vomiting, nausea, depression, anxiety, addiction, mood or behavioral disorder, schizophrenia, sleep disorder, restless leg syndrome, learning or memory disorder, sexual or psychosexual dysfunction, pain, visceral or neuropathic pain, hyperalgesia, allodynia, digestive disorder, irritable bowel syndrome, neuronal degeneration, ischemic or hemorrhagic strokes, Cushing's disease, Guillain-Barré syndrome, myotonic dystrophy, urinary incontinence, hyperthyroidism, disorder of pituitary function, hypertension or hypotension, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 2 , or an addition salt with an acid thereof, or a hydrate or solvate thereof. 
   
   
       8 . A method for treating obesity, appetite or taste disturbance, cachexia, anorexia, bulimia, diabetes, metabolic syndrome, vomiting, nausea, depression, anxiety, addiction, mood or behavioral disorder, schizophrenia, sleep disorder, restless leg syndrome, learning or memory disorder, sexual or psychosexual dysfunction, pain, visceral or neuropathic pain, hyperalgesia, allodynia, digestive disorder, irritable bowel syndrome, neuronal degeneration, ischemic or hemorrhagic strokes, Cushing's disease, Guillain-Barré syndrome, myotonic dystrophy, urinary incontinence, hyperthyroidism, disorder of pituitary function, hypertension or hypotension, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 3 , or an addition salt with an acid thereof, or a hydrate or solvate thereof. 
   
   
       9 . A pharmaceutical composition comprising the compound according to  claim 1 , or an addition salt with an acid thereof, or a hydrate or solvate thereof, in combination with at least one pharmaceutically acceptable excipient. 
   
   
       10 . A pharmaceutical composition comprising the compound according to  claim 2 , or an addition salt with an acid thereof, or a hydrate or solvate thereof, in combination with at least one pharmaceutically acceptable excipient. 
   
   
       11 . A pharmaceutical composition comprising the compound according to  claim 3 , or an addition salt with an acid thereof, or a hydrate or solvate thereof, in combination with at least one pharmaceutically acceptable excipient.